Much progress has been made in recent years in the preparation of forms for oral administration of medicaments with a view toward better control of the kinetics of release of medicament. Coating materials have been developed, as have manners to retain the medicament in inert matrices and manners for diffusion or controlled dialysis of medicaments. Recourse has even been had to the combination of several of these forms to ensure, starting from the same pharmaceutical form, a modification of the absorption or of the elimination of the medicaments in order to prolong the time of action thereof, as in the case, for example, of the association in the same medicament of viscosifying agents which retard the dissolving process with active constituents of well determined granulometry. The improvements which have been introduced in the preparation of pharmaceutical forms for oral administration with a prolonged action, are manifested principally (1) in a fractionation in the same medicament unit (capsule, tablet, granule) of the total dose into several small doses coated with suitable excipients which are made available to the organism at the desired time, (2) in the retention of the medicament in a sort of inert matrix which is very slowly splittable, in a form which is called upon to diffuse its contents gradually according to predetermined kinetics, and (3) in the fixing of the medicaments to several adjuvants so as to obtain insoluble complexes from which the medicaments are eluted slowly and supplied to the organism according to predetermined kinetics.
The various coatings and coating films depend evidently on the physiological factors (enzymatic activity, pH, etc.) which exist in the gastro-intestinal tract; these factors (and more particularly, the pH) vary not only throughout the gastro-intestinal tract, but also from one person to another. The possibility of controlling the release of the active principle throughout the course of the medicament in the gastro-intestinal tract assumes the first place that it is possible to control the solubility of the medicament at each moment of this process. The solubility of the majority of medicaments (if not all) varies precisely as a function of the pH.
Until now, the addition of application solutions of excipients and of coatings, constituted by polyvinylpyrrolidone, gum-lacquer, waxes, syrups, etc., has been used as a means for moistening the pellets or tablets of sugar or the pellets and/or the tablets of active principle to cause the adherence thereto of subsequent layers of active component. It is precisely by the modification of these application solutions that the object envisaged by Applicant has been obtained.
To overcome this drawback, it has been known to add a solid pH adjusting compound to the active component in an attempt to adjust the pH around the medicament and improve the release of the active principle. However, except in the case of granules obtained by high compression (see British patent 2,039,737), this solid product does not exert its action completely in vivo since the dissolution into the stomach is not always complete and steady so that the drug is already absorbed through the gastro-intestinal tract when the optimum pH is finally attained in the stomach.